Method of treating diabetes mellitus using arylglyoxals

ABSTRACT

A method of treating diabetes mellitus using arylglyoxals which are known compounds.

BACKGROUND OF THE INVENTION

This invention relates to a method of treating diabetes mellitus using arylglyoxals and various hydrates and adducts formed from them. These compounds are either known in the art per se or are homologs or derivatives of compounds disclosed in the art. All the compounds of this invention are known in the art to have an unrelated pharmaceutical activity, or there is a disclosure of inactivity. The compounds of this invention are hypoglycemic agents capable of ameliorating diabetes mellitus in mammals by acting to simulate and/or potentiate the action of insulin. This invention further relates to pharmaceutical compositions for the utilization of these compounds in the treatment of diabetes mellitus. Further, this invention relates to the chemical synthesis of the compounds disclosed herein.

The disease diabetes mellitus is characterized by metabolic defects in the production and utilization of glucose which result in the failure to maintain appropriate blood sugar levels. The result of this defect is elevated blood glucose or hyperglycemia. Research on the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Treatments have included parenteral administration of exogenous insulin, oral administration of drugs, and dietary therapies.

Initially it was thought that hyperglycemia was simply the result of a deficiency in the supply of insulin, the principle hormone which controls glucose metabolism. As a result, research focused on the source of insulin production, the beta cells of the pancreas, and pharmaceutical agents were discovered which stimulated the production of insulin by the pancreas. Although it remains true that a deficiency of insulin does cause hyperglycemia it has now been recognized that other metabolic defects can be a major cause of elevated blood glucose.

In Type I diabetes, also called juvenile onset or insulin-dependent diabetes, insulin deficiency is indeed the cause of hyperglycemia. However, the majority of diabetics suffer from a form of the disease referred to as Type II diabetes, also called maturity onset or non-insulin dependent diabetes. A main characteristic displayed by Type II diabetics is insulin resistance or insulin insensitivity. Insulin resistance is a condition in which available insulin, secreted by the pancreas and circulating in the blood stream, fails to stimulate sufficient glucose uptake and utilization in insulin-sensitive tissue. This inability of certain tissues including liver, muscle, and fat, whose metabolic machinery is normally sensitive to insulin, to utilize glucose efficiently or to control endogenous glucose synthesis and glycogenolysis, results in elevated blood glucose.

Compounds which simulate and/or potentiate the biological action of insulin would be beneficial in the treatment of hyperglycemia resulting from mild to moderate insulin insufficiency or insulin insensitivity. A compound which would simulate or mimic insulin's action would correct both insulin deficiency and insulin resistance by its own insulin-like action. Further, a compound which would potentiate insulin's action would ameliorate insulin deficiency by rendering the small amount of insulin which is present more efficacious and would decrease insulin resistance directly by acting synergistically to make insulin more effective. Thus compounds which show insulin-like and/or insulin potentiating activity would be beneficial for the treatment of hypoglycemia occuring either in Type I or Type II diabetes.

The compounds of the present invention simulate and potentiate the biological action of insulin. They simulate insulin's action at least in part by promoting the cellular uptake and metabolism of glucose in the absence of insulin. They potentiate insulin's action by exerting a synergistic effect on insulin action in the presence of sub-maximal concentrations of insulin. The exact mechanism by which the compounds of the invention act to produce these effect is not known and the invention should not be construed as limited to any particular mechanism of action. Nonetheless, the compounds of this invention are useful for the treatment of hyperglycemia and diabetes in mammals.

BRIEF SUMMARY OF THE INVENTION

This invention is concerned with a method of treating diabetes mellitus with compounds which may be represented by the following structural formula: ##STR1## wherein A is selected from the group consisting of phenyl, 2-fluorenyl, 2-naphthyl, 2-dibenzofuranyl, 2-dibenzothienyl, 2-phenoxathiinyl, 2-phenanthryl, 3-phenanthryl, 9-phenanthryl, 2-thiophene, 2-thienyl and 9-anthracene; R₁ may be substituted meta or para to the aryl-carbonyl bond is selected from the group consisting of hydrogen, halogen, (C₁ -C₂₀)alkyl, (C₁ -C₂₀)alkoxy, cycloalkyl, phenyl, phenoxy, phenylthio, benzyl, (C₁ -C₂₀)alkyamino, substituted phenyl wherein the substituents are halogen, (C₁ -C₆)alkyl or (C₁ -C₆)alkoxy, substituted phenoxy wherein the substituents are halogen, (C₁ -C₆)alkyl or (C₁ -C₆)alkoxy, and substituted phenylthio wherein the substituents are halogen, (C₁ -C₆)alkyl or (C₁ -C₆)alkoxy; R₂ is selected from the group consisting of hydrogen and (C₁ -C₆)alkoxy; X and Y may be the same or different and are independently selected from the group consisting of hydroxy, (C₁ -C₆)alkoxy, anilino, carboxyanilino, ##STR2## and --SO₃ Q wherein Q is an alkali metal or alkaline earth metal, with the proviso that X and Y taken together may represent oxygen; and the hydrates thereof.

This invention also relates to a method of treating hyperglycemia in a mammal in need of such treatment which comprises administering to said mammal an effective amount of a compound of the above-described formula.

This invention also relates to a pharmaceutical composition which comprises an effective antidiabetic amount of a compound of the above-described formula, in association with a pharmaceutically acceptable carrier.

This invention also relates to a pharmaceutical composition which comprises an effective hypoglycemic amount of a compound of the above-described formula in association with a pharmaceutically acceptable carrier.

Finally, this invention relates to processes for preparing compounds of the above-described formula.

In a more preferred embodiment, this invention is concerned with a method of treating diabetes mellitus with compounds represented by the above general formula wherein A is as described above; R₁ may be substituted meta or para to the aryl-carbonyl bond and is selected from the group consisting of hydrogen, chloro, fluoro, bromo, (C₃ -C₁₆)alkyl, (C₃ -C₁₆)alkoxy, cyclohexyl, phenyl, phenoxy, phenylthio, benzyl, (C₄ -C₁₆)alkylamino, substituted phenyl wherein the substituents are selected from the group consisting of chloro, fluoro, bromo, methyl and methoxy; substituted phenoxy wherein the substituents are selected from the group consisting of chloro, fluoro, bromo, (C₁ -C₄)alkyl and methoxy, substituted phenylthio wherein the substituents are selected from the group consisting of fluoro, chloro, (C₁ -C₄)alkyl and methoxy; R₂ is selected from the group consisting of hydrogen and methoxy; X and Y may be the same or different and are independently selected from the group consisting of hydroxy, ethoxy, carboxyanilino, ##STR3## and --SO₃ Na, with the proviso that X and Y taken together may represent oxygen; and the hydrates thereof.

DETAILED DESCRIPTION OF THE INVENTION

Certain of the compounds of this invention may be prepared according to the following reaction sequence: ##STR4## A ketone (1) is dissolved in dimethyl sulfoxide and treated with hydrobromic acid at 45°-65° C. for 18-48 hours. The mixture is poured into ice and extracted with ethyl acetate. The extract is concentrated, dissolved in a mixture of ethanol and water at 50°-70° C. and treated with sodium metabisulfite at the boiling point for 5 minutes, then cooled under argon at 0° C., giving (3) where R₁, R₂, and A are as described above. The methanesulfonic acid, sodium salt derivative (3) is then suspended in water at 40°-60° C., acidified, heated at 90°-100° C. for 1-2 hours, cooled and extracted with diethyl ether. The ether is concentrated giving (2) where R₁, R₂, and A are as described above. Compounds of structure (2) are obtained in various degrees of hydration; that is, n may vary from almost zero to one or more. Alternatively, the ketone (1), where R.sub. 1, R₂, and A are as described above, is treated with selenium dioxide in aqueous dioxane at reflux, under an inert atmosphere for 12-24 hours. The reaction is then filtered and the filtrate evaporated, giving (2) where R₁, R₂, and A are as described above which may be converted to the methanesulfonic acid, sodium salt derivative (3) by treatment with sodium metabisulfite in aqueous ethanol.

The compounds of this invention were tested for their insulin-like and insulin-potentiating activity according to the following procedure: Male, Wistar strain, Royal Hart rats weighing 125-170 g. were sacrificed by decapitation. Their abdominal cavities were opened and distal or thin portions of epididymal fat pads excised, accumulated, and placed in 0.9% saline. The tissue was weighed and placed at a density of about 0.4 g/ml in Krebs-Henseleit bicarbonate (KHB) buffer containing 5 mg. of crude bacterial collagenease per ml. [The KHB is composed of 118 mM sodium chloride; 4.7 mM potassium chloride; 1.2 mM calcium chloride; 1.2 mM potassium dihydrogen phosphate; 1.2 mM magnesium sulfate heptahydrate; 25 mM sodium bicarbonate and 0.3 mM glucose and is saturated with oxygen:carbon dioxide (95:5).] The tissues were incubated with collagenase for one hour at 37° C. with gentle agitation in a Dubnoff metabolic shaker. At the end of this digestion period the cells were washed five times with twice their volume of KHB buffer containing fatty acid free bovine serum albumin (Pentex Fraction V) at a concentration of 3%. The digest was filtered through two layers of gauze and suspended in KHB buffer with albumin to a volume ten times the initial total weight of the fat pads. Incubation of one ml. aliquots of the cell suspension was carried out in 17×100 mm plastic Falcon tubes. Cells were incubated in the presence or absence of test compound and insulin. All tubes contained 0.15 μCi D-glucose-U-¹⁴ C (specific activity 200 mC/mmole).

Recrystallized porcine insulin (specific activity =25.5 U/mg) was dissolved in 0.9% saline adjusted to pH 3 with hydrochloric acid. The insulin was added to the cells at a concentration of approximately 5 μU/ml and control or basal cells received comparable volumes of pH 3 saline. Test compounds were dissolved in 50% dimethylsulfoxide-50% ethanol and added to the cells at a concentration of 100 μg/ ml. Control cells received comparable volumes of dimethyl sulfoxide-ethanol.

After the tubes were loaded with insulin and test compound, or other vehicles, and cell suspension, they were capped with sleeve stoppers fitted with hanging, plastic center wells. Each well contained a small section of folded filter paper. The tubes were then gassed for about one minute with oxygen:carbon dioxide (95:5) via needles inserted through the septum of the stopper. Immediately after gassing, the radioactive glucose was injected into the incubate and the tubes were placed in a 37° C. metabolic shaking water bath and were incubated for one hour with gentle agitation.

At the end of the incubation, 0.4 ml. of Hyamine hydroxide and then 0.5 ml. of 5N sulfuric acid were carefully injected into the center well and cell suspension, respectively. The acidified cell suspension was then incubated an additional 30 minutes at room temperature with gentle agitation. At the end of this carbon dioxide collection period, the center wells were dropped into vials containing 10 ml. of Dimiscint® scintillation cocktail and the radioactivity counted by liquid scintillation spectrometry.

The measurement of carbon dioxide radioactivity in counts per minute produced by these cells in the absence of both test compound and insulin is the basal level (b). Radioactivity produced in the presence of test compounds only, insulin only and both test compound and insulin are (c), (i) and (ci), respectively. Each of (c), (i) and (ci) is then expressed as a percent of the basal value: C=(c/b); I=(i/b); CI=(ci/b). Finally, insulin-like activity (%C/I) is calculated using the formula ##EQU1## and insulin-potentiating activity (%P) is calculated using the formula ##EQU2##

The results of this test on representative compounds of this invention appear in Table I.

                  TABLE I                                                          ______________________________________                                                                    %      %                                            Compound                   C/I    P                                            ______________________________________                                         4-biphenylglyoxal hemihydrate                                                                             448    174                                          p-[α-hydroxy-p-phenylphenacyl)amino]-benzoic                                                        166    222                                          acid                                                                           p-[(α-ethoxy-p-phenylphenacyl)amino]-benzoic                                                        119    244                                          acid                                                                           (4-biphenylcarbonyl)hydroxy-methanesulfonic                                                               165    125                                          acid, sodium salt                                                              phenylglyoxal              120    68                                           p-chlorophenylglyoxal      357    122                                          benzoylhydroxy-methanesulfonic acid, sodium                                                               138    16                                           salt                                                                           4'-(p-chlorophenyl)-2,2-dihydroxy-acetophenone                                                            572    0                                            4'-chloro-α-hydroxy-β-oxo-4-biphenylethane-                                                    173    93                                           sulfonic acid, sodium salt                                                     4'-heptyl-2,2-dihydroxy-acetophenone                                                                      525    86                                           p-cyclohexylbenzoylhydroxy-methanesulfonic                                                                612    33                                           acid, sodium salt                                                              4-cyclohexyl-2,2-dihydroxy-acetophenone                                                                   788    0                                            p-heptylbenzoylhydroxy-methanesulfonic acid,                                                              315    241                                          sodium salt                                                                    hydroxy(p-phenoxybenzoyl)-methanesulfonic                                                                 188    259                                          acid, sodium salt                                                              2,2-dihydroxy-4'-phenoxy-acetophenone                                                                     422    246                                          hydroxy(4'-methoxy-4-biphenylcarbonyl)-                                                                   86     0                                            methanesulfonic acid, sodium salt                                              (4'-fluoro-4-biphenylcarbonyl)hydroxy-                                                                    281    132                                          methanesulfonic acid, sodium salt                                              2,2-dihdroxy-4'-p-tolyl-acetophenone                                                                      240    141                                          2-fluorenyl-dihydroxymethyl ketone                                                                        304    131                                          p-[[hydroxy(2-naphthoyl)methyl]amino]-benzoic                                                             371    190                                          acid                                                                           hydroxy(4'-methyl-4-biphenylcarbonyl)-                                                                    57     49                                           methanesulfonic acid, sodium salt                                              α-hydroxy-β-oxo-fluorene-2-ethanesulfonic                                                      73     131                                          acid, sodium salt                                                              α-hydroxy-β-oxo-2-dibenzofuranethanesulfonic                                                   130    133                                          acid, sodium salt                                                              α-hydroxy-β-oxo-2-phenoxathiinethanesulfonic                                                   50     15                                           acid, sodium salt                                                              dihydroxymethyl-2-phenoxathiinyl ketone                                                                   185    56                                           p-bromobenzoylhydroxy-methanesulfonic acid,                                                               31     124                                          sodium salt                                                                    α-hydroxy-β-oxo-3-biphenylethanesulfonic                                                       494    293                                          acid, sodium salt                                                              4'-(o-bromophenyl)-2,2-dihydroxy-acetophenone                                                             356    152                                          2'-chloro-α-hydroxy-β-oxo-4-biphenylethane-                                                    163    123                                          sulfonic acid, sodium salt                                                     2-dibenzofuranyloxylaldehyde                                                                              75     75                                           2-dibenzothienyl-ethoxyhydroxymethyl ketone                                                               389    0                                            α-hydroxy-β-oxo-2-benzothiopheneethanesulfonic                                                 193    120                                          acid, sodium salt                                                              α-hydroxy-β-oxo-9-phenanthreneethanesulfonic                                                   39     37                                           acid, sodium salt                                                              dihydroxymethyl-9-phenanthryl ketone                                                                      99     0                                            N--(α-hydroxy-p-phenylphenacyl)-sulfanilic                                                          39     81                                           acid, sodium salt                                                              α-hydroxy-6-methoxy-β-oxo-3-biphenylethane-                                                    124    49                                           sulfonic acid, sodium salt                                                     dihydroxymethyl-3-phenanthryl ketone                                                                      357    93                                           α-hydroxy-β-oxo-9-anthraceneethanesulfonic                                                     39     0                                            acid, sodium salt                                                              α-hydroxy-β-oxo-2-phenanthreneethanesulfonic                                                   111    38                                           acid, sodium salt                                                              2-thiopheneglyoxylaldehyde 40     0                                            dihydroxymethyl-5-phenyl-2-thienyl ketone                                                                 220    0                                            α-hydroxy-β-oxo-3-phenanthreneethanesulfonic                                                   140    68                                           acid, sodium salt                                                              α-hydroxy-β-oxo-5-phenyl-2-thiopheneethane-                                                    163    25                                           sulfonic acid sodium salt                                                      hydroxy[p-(phenylthio)benzoyl]-methanesulfonic                                                            90     201                                          acid, sodium salt                                                              (p-chlorobenzoyl)hydroxy-methanesulfonic acid,                                                            164    122                                          sodium salt                                                                    (p-benzylphenyl)glyoxylaldehyde                                                                           245    127                                          p-benzylbenzoxylhydroxy-methanesulfonic acid,                                                             62     137                                          sodium salt                                                                    dihydroxymethyl-2-phenanthryl ketone                                                                      153    34                                           4'-(p-chlorophenoxy)-2,2-dihydroxy-aceto-                                                                 285    44                                           phenone                                                                        [p-(p-chlorophenoxy)benzoyl]hydroxy-methane-                                                              87     136                                          sulfonic acid, sodium salt                                                     [p-(p-tert.-butylphenoxy)benzoyl]hydroxy-                                                                 119    55                                           methanesulfonic acid, sodium salt                                              (p-fluorophenyl)-glyoxal   85     10                                           p-fluorobenzoylhydroxy-methanesulfonic acid,                                                              116    71                                           sodium salt                                                                    p-anisoylhydroxy-methanesulfonic acid,                                                                    67     0                                            sodium salt                                                                    [p-(decyloxy)phenyl]-glyoxal                                                                              398    159                                          4'-(hexadecyloxy)-2,2-dihydroxy-acetophenone                                                              64     106                                          4'-(p-tert.-butylphenoxy)-2,2-dihydroxy-                                                                  671    214                                          acetophenone                                                                   [p-(p-fluorophenoxy)phenyl]-glyoxal                                                                       698    192                                          2,2-dihydroxy-4'-(p-methoxyphenoxy)-                                                                      414    78                                           acetophenone                                                                   hydroxy[p-(p-methoxyphenoxy)benzoyl]-methane                                                              163    79                                           sulfonic acid, sodium salt                                                     2,2-dihydroxy-4'-methoxy-acetophenone                                                                     172    178                                          [p-(decyloxy)benzoyl]hydroxy-methanesulfonic                                                              433    282                                          acid, sodium salt                                                              (p-butoxyphenyl)glyoxal    672    266                                          p-butoxybenzoylhydroxy-methanesulfonic acid,                                                              296    350                                          sodium salt                                                                    [p-(p-fluorophenoxy)benzoyl]hydroxy-methane                                                               458    309                                          sulfonic acid, sodium salt                                                     p-[[2-(2-dibenzofuranyl)-1-hydroxy-2-                                                                     334    136                                          oxoethyl]amino]benzoic acid                                                    4'-(p-bromophenoxy)-2,2-dihydroxy-acetophenone                                                            297    216                                          [p-(p-tert.-butylphenylthio)benzoyl]hydroxy-                                                              79     46                                           methanesulfonic acid, sodium salt                                              hydroxy[p-(p-methoxyphenylthio)benzoyl]-                                                                  139    158                                          methanesulfonic acid, sodium salt                                              [p-(hexadecyloxy)benzoyl]hydroxy-methane                                                                  198    275                                          sulfonic acid, sodium salt                                                     [p-(decylamino)benzoyl]hydroxy-methanesulfonic                                                            166    146                                          acid, sodium salt                                                              hydroxy[p-(m-tolyloxy)benzoyl]-methanesulfonic                                                            400    548                                          acid, sodium salt                                                              hydroxy(p-tolyloxybenzoyl)-methanesulfonic                                                                113    162                                          acid, sodium salt                                                              [p-(p-fluorophenylthio)benzoyl]hydroxy-                                                                   367    493                                          methanesulfonic acid, sodium salt                                              [p-(m-chlorophenoxy)benzoyl]hydroxy-methane-                                                              528    550                                          sulfonic acid, sodium salt                                                     hydroxy[p-(p-tolylthio)benzoyl]-methane                                                                   227    348                                          sulfonic acid, sodium salt                                                     2,2-dihydroxy-4'-p-tolyloxy-acetophenone                                                                  580    188                                          2,2-dihydroxy-4'-m-tolyloxy-acetophenone                                                                  1032   188                                          hydroxy[p-(m-methoxyphenoxy)benzoyl]-methane-                                                             53     127                                          sulfonic acid, sodium salt                                                     hydroxy(p-propoxybenzoyl)-methanesulfonic                                                                 254    185                                          acid, sodium salt                                                              (p-aminobutylbenzoyl)hydroxy-methanesulfonic                                                              133    132                                          acid, sodium salt                                                              [p-(p-chlorophenylthio)benzoyl]hydroxy-                                                                   156    263                                          methanesulfonic acid, sodium salt                                              [p-(m-fluorophenoxy)benzoyl]hydroxy-methane-                                                              208    399                                          sulfonic acid, sodium salt                                                     hydroxy(p-pentyloxybenzoyl)-methanesulfonic                                                               582    644                                          acid, sodium salt                                                              2,2-dihydroxy-4'-propoxy-acetophenone                                                                     227    89                                           4'-(m-chlorophenoxy)-2,2-dihydroxy-                                                                       751    283                                          acetophenone                                                                   o-bromobenzoylhydroxy-methanesulfonic acid,                                                               88     59                                           sodium salt                                                                    2,2-dihydroxy-4'-(octyloxy)-acetophenone                                                                  761    283                                          2,2-dihydroxy-4'-(isopentyloxy)-acetophenone                                                              463    169                                          4'-hexadecylamino-2,2-dihydroxy-acetophenone                                                              273    175                                          α-hydroxy-3-(4-methylphenoxy)-β-oxo-                                                           83     113                                          benzeneethanesulfonic acid, sodium salt                                        4-(decylamino)-α-oxo-benzeneacetaldehyde                                                            349    29                                           4-(hexadecylamino)-α-hydroxy-β-oxo-                                                            446    391                                          benzeneethanesulfonic acid, sodium salt                                        [p-(p-bromophenoxy)benzoyl]hydroxy-methane-                                                               57     158                                          sulfonic acid, sodium salt                                                     hydroxy[p-(octyloxy)benzoyl]-methanesulfonic                                                              223    77                                           acid, sodium salt                                                              3-[4-(1,1-dimethylethyl)phenoxy]-α-hydroxy-                                                         135    107                                          β-oxo-benzeneethanesulfonic acid, sodium salt                             hydroxy[p-(isopentyloxy)benzoyl]-methane-                                                                 250    315                                          sulfonic acid, sodium salt                                                     ______________________________________                                    

When the compounds are employed for the above utility, they may be combined with one or more pharmaceutically acceptable carriers, e.g., solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.5 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.5 to 5% suspending agent in an isotonic medium. These pharmaceutical preparations may contain, for example, from about 0.5% up to about 90% of the active ingredient in combination with the carrier, more usually between 5% and 60% by weight.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 5 milligrams to about 100 milligrams per kilogram of animal body weight, preferably given in divided doses two to four times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 500 milligrams to about 5,000 milligrams preferably from about 350 milligrams to 3,500 milligrams. Dosage forms suitable for internal use comprise from about 25 to 500 milligrams of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapetuic situation. A decided practical advantage is that these active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes if necessary. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, e.g., vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the stand-point of ease of preparation and administration are solid composition, particularly tablets and hard-filled or liquid-fiiled capsules. Oral administration of the compounds is preferred.

These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

The invention will be more fully described in conjunction with the following specific examples which are not to be construed as limiting the scope of the invention.

EXAMPLE 1 4'-Propoxyacetophenone

A mixture of 12.3 g. of 1-propyl bromide, 13.6 g. of 4-hydroxyacetophenone, 27.6 g. of potassium carbonate and 200 ml. of acetone was refluxed overnight. The mixture was then cooled, filtered, the filtrate concentrated and distilled in a Kugelrohr. The distillate was dissolved in ethyl acetate, treated with charcoal, filtered through diatomaceous earth, concentrated and dried, giving the desired intermediate as an oil.

Following essentially the procedure of Example 1, but employing other starting materials, the intermediates of Examples 2-18 (Table II) were obtained.

                  TABLE II                                                         ______________________________________                                         Ex-                                                                            am-                         Physical                                           ple  Intermediate           Constant                                           ______________________________________                                          2   4'-(decyloxy)acetophenone                                                                             mp    35-36° C.                              3   4'(phenylthio)acetophenone                                                                            mp    66.5-68.5° C.                          4   4'-(p-methoxyphenoxy)acetophenone                                                                     mp    48-51                                         5   4'(p-bromophenoxy)acetophenone                                                                        mp    67-73° C.                              6   4'-(p-tert-butylpheylthio)-                                                                           mp    48-51°                                     acetophenone                                                               7   4'-(p-methoxylphenythio)-                                                                             mp    31-34° C.                                  acetophenone                                                               8   4'-(p-fluorophenylthio)-                                                                              mp    62-68° C.                                  acetophenone                                                               9   4'-(m-chlorophenoxy)acetophenone                                                                      bp    156-158° C.                           10   4'-butylaminoacetophenone                                                                             mp    78-81° C.                             11   4'-(p-chlorophenylthio)-                                                                              mp    45-50° C.                                  acetophenone                                                              12   4'-n-hexadecyloxyacetophenone                                                                         mp    62-64° C.                             13   4'-m-tolyloxy)acetophenone                                                                            bp    143-145° C.                           14   4'-(p-tolylthio)acetophenone                                                                          mp    81-85° C.                             15   4'-(p-tolyloxy)acetophenone                                                                           mp    41-44° C.                             16   4'-(p-octyloxy)acetophenone                                                                           mp    27-29°                                17   4'-(isopentyloxy)acetophenone                                                                               oil                                          18   4'-(m-fluorophenoxy)acetophenone                                                                      bp    131° C.                               ______________________________________                                    

EXAMPLE 19 2-Bromo-4'(-p-tolyl)acetophenone

An 11.7 g. portion of 4-methylbiphenyl was dissolved in 75 ml. of carbon disulfide and cooled in an ice bath while 11.6 g. of aluminum chloride was added portionwise with vigorous stirring. A 15.9 g. portion of bromoacetylbromide was added dropwise and after completion and the reaction subsided the mixture was heated at reflux for 3 hours, then cooled overnight. The mixture was poured into crushed ice and 150 ml. of acetic acid and stirred for 1.5 hours. The resulting gum was collected and stirred in methanol for 2 hours, giving a solid. This solid was dissolved in methanol:acetone, treated with charcoal and cooled. The solution was decanted, concentrated to about 150 ml., decanted and recooled giving a solid which was collected, giving the desired intermediate as a beige solid, m.p. 120°-122° C.

Following essentially the procedure of Example 19, but employing other starting materials, the intermediates of Examples 20-30 (Table III) were obtained.

                  TABLE III                                                        ______________________________________                                                                     Physical                                           Example                                                                               Intermediate         Constant                                           ______________________________________                                         20     2-bromo-4'-(p-fluorophenyl)-                                                                        mp    98.5-99.5° C.                                acetophenone                                                            21     4'-(p-methoxyphenyl)acetophenone                                                                    mp    148-154° C.                           22     2-bromo-4'-(p-chlorophenyl)-                                                                        mp    124-126° C.                                  acetophenone                                                            23     2-bromo-4'-cyclohexylacetophenone                                                                   mp    37.5-38° C.                           24     2-bromo-4'-heptylacetophenone                                                                       mp    35-36° C.                             25     4'-benzylacetophenone                                                                               bp    130-133° C.                           26     2-bromo-4'-(O--bromophenyl)-                                                                              oil                                                 acetophenone                                                            27     2-dibenzothienyl methyl ketone                                                                      mp    99-103° C.                            28     2-xanthenyl methyl ketone                                                                           mp    106-109° C.                           29     2-bromo-4'-methoxy-3'-phenyl-                                                                       mp    76-77° C.                                    acetophenone                                                            30     2-dibenzofuranyl methyl ketone                                                                      mp    71-72° C.                             ______________________________________                                    

EXAMPLE 31 [p-(Decyloxy)phenyl]glyoxal

A mixture of 11.56 g. of 4'-(decyloxy)acetophenone, 4.6 g. of selenium dioxide, 150 ml. of dioxane and 4 ml. of water was refluxed overnight, filtered through diatomaceous earth, washed with dioxane and the filtrate evaporated to dryness. The residue was triturated with water, dried and crystallized from 150 ml. of hot acetone giving the desired product as an off-white solid, m.p. 81°-83° C.

EXAMPLE 32 [p-(decyloxy)benzoyl]hydroxymethanesulfonic acid, sodium salt

To a warm solution of 4.0 g. of [p-(decyloxy)phenyl]glyoxal in 150 ml. of ethanol was added a solution of 1.045 g. of sodium metabisulfite in 20 ml. of water. The mixture was allowed to stand overnight and then the solid was collected, washed with acetone and dried. This solid was crystallized twice from a mixture of acetone:water (1.1), giving the desired product as a white solid.

EXAMPLE 33 Hydroxy[p-(isopentyloxy)benzoyl]methanesulfonic acid, sodium salt

A mixture of 9.4 g. of 4'-(isopentyloxy)acetophenone, 7.7 ml. of 48% hydrobromic acid and 38 ml. of dimethyl sulfoxide was stirred at 60° C. for 67 hours. The mixture was then cooled, poured into 200 ml. of ice water, 100 ml. of water was added and the solid was collected and washed with water. This solid was dissolved in acetone, filtered and precipitated by the addition of water. This solid was dissolved in 150 ml. of ethanol and a solution of 4.0 g. of sodium metabisulfite in 125 ml. of water, warmed and stirred for 2 hours, then stirred at room temperature overnight. The solid was collected giving the desired product.

EXAMPLE 34 2,2-dihydroxy-4'-(isopentyloxy)acetophenone

A 6.0 g. portion of hydroxy [p-(isopentyloxy)benzoyl]methanesulfonic acid, sodium salt was dissolved in a mixture of 100 ml. of 0.5N hydrochloric acid and 15 ml. of acetone. The solid was collected, giving the desired product, m.p. 80°-85° C.

Reaction of the intermediates of Examples 1-30, as well as other commercially available acetophenone derivatives and acetophenone derivatives made by the general procedures of Examples 1 and 19 according to the procedures of Examples 31-34, gave the products of Examples 35-115 (Table IV).

                                      TABLE IV                                     __________________________________________________________________________          Intermediate               Physical                                       Example                                                                             Derivation                                                                            Product             Constant                                       __________________________________________________________________________     35   4-acetylbi-                                                                           4-biphenylglyoxal hemihydrate                                                                      mp 104-109° C.                               phenyl                                                                    36   Phenyl-                                                                               benzoylhydroxy-methanesulfonic acid,                                                               mp 174-180° C.                               glyoxal                                                                               sodium salt                                                        37   p-phenoxy-                                                                            2,2-dihydroxy-4'-phenoxyacetophenone                                                               mp  73-80° C.                                acetophenone                                                              38    37    hydroxy (p-phenoxybenzoyl)-methane-                                                                mp 170-180° C.                                      sulfonic acid, sodium salt                                         39    21    hydroxy (4'-methoxy-4-biphenylcar-                                                                 mp 205-220° C.                                      bonyl)-methanesulfonic acid, sodium salt                           40    20    (4'-fluoro-4-biphenylcarbonyl)hydroxy-                                                             mp 195-205° C.                                      methanesulfonic acid, sodium salt                                  41   2-acetyl-                                                                             2-fluorenyl dihydroxymethyl ketone                                                                 mp 110-125° C.                               fluorene                                                                  42    41    α-hydroxy-β-oxo-fluorene-2-ethane-                                                      mp 250° C.                                          sulfonic acid, sodium salt                                         43    30    α-hydroxy-β-oxo-2-dibenzofuranethane-                                                   mp <300° C.                                         sulfonic acid, sodium salt                                         44    28    α-hydroxy-β-oxo-2-phenoxathiinethane-                                                   mp <300°                                            sulfonic acid, sodium salt                                         45    44    dihydroxymethyl 2-phenoxathiinyl ketone                                                            mp 125-128° C.                          46   3-acetylbi-                                                                           α-hydroxy-β-oxo-3-biphenylethane-                                                       mp 190-198° C.                               phenyl sulfonic acid, sodium salt                                         47    30    2-dibenzofuranglyoxylaldehyde                                                                      mp 120-123°  C.                         48    27    2-dibenzothienyl ethoxyhydroxymethyl                                                               mp  82-85° C.                                       ketone                                                             49    48    α-hydroxy-β-oxo-2-benzothiophene-                                                       mp 210-220° C.                                      ethanesulfonic acid, sodium salt                                   50   9-acetyl-                                                                             α-hydroxy-β-oxo-9-phenanthreneethane-                                                   mp 185° C.                                   phenanthrene                                                                          sulfonic acid, sodium salt                                                                         (dec.)                                         51    50    dihydroxymethyl 9-phenanthryl ketone                                                               mp  94-100° C.                          52    29    α-hydroxy-6-methoxy-β-oxo-3-biphenyl-                                                   mp 173° C.                                          ethanesulfonic acid, sodium salt                                   53   3-acetyl-                                                                             α-hydroxy-β-oxo-3-phenanthreneethane-                                                   white solid                                         phenanthrene                                                                          sulfonic acid, sodium salt                                         54    53    dihydroxymethyl-3-phenanthryl ketone                                                               mp  98-104° C.                          55   9-acetyl-                                                                             α-hydroxy-β-oxo-9-anthraceneethane-                                                     mp 180-200° C.                               anthracene                                                                            sulfonic acid, sodium salt                                         56   2-acetyl-                                                                             α-hydroxy-β-oxo-2-phenanthreneethane-                                                   white solid                                         phenanthrene                                                                          sulfonic acid, sodium salt                                         57    56    dihydroxymethyl 2-phenanthryl ketone                                                               white solid                                    58   2-acetyl-                                                                             2-thiopheneglyoxylaldehyde                                                                         mp  90-91° C.                                thiophene                                                                 59     3    hydroxy [p-(phenylthio)benzoyl]-methane-                                                           white solid                                                sulfonic acid, sodium salt                                         60    25    (p-benzylphenyl)gloxylaldehyde                                                                     mp 103-110° C.                          61    60    p-benzlbenzyoxylhydroxy-methanesulfonic                                                            mp 280-300° C.                                      acid, sodium salt   (dec.)                                         62   p-chloro-                                                                             4'-(p-chlorophenoxy)-2,2-dihydroxy-                                                                mp 109-122° C.                               phenoxy                                                                               acetophenone                                                            acetophenone                                                              63    62    [p-(p-chlorophenoxy)benzoyl]hydroxy-                                                               mp <300° C.                                         methanesulfonic acid, sodium salt                                  64   p-tert-                                                                               [p-(p-tert-butylphenoxy)benzoyl]-                                                                  mp 190-230° C.                               butylphenoxy                                                                          hydroxy-methanesulfonic acid, sodium                                                               (dec.)                                              acetophenone                                                                          salt                                                               65    64    4'-(p-tert-butylphenoxy)-2,2-dihydroxy-                                                            mp  82-87° C.                                       acetophenone                                                       66   p-fluoro-                                                                             (p-fluorophenyl)-glyoxal                                                                           mp  93-98° C.                                acetophenone                                                              67    66    p-fluorobenzoylhydroxy-methanesulfonic                                                             mp 300° C.                                          acid, sodium salt                                                  68   4-methoxy                                                                             p-anisoylhydroxy-methanesulfonic acid,                                                             white solid                                         acetophenone                                                                          sodium salt                                                        69    68    2,2-dihydroxy-4'-methoxy-acetophenone                                                              mp  79-81° C.                           70    12    4'-(hexadecyloxy)-2,2-dihydroxy-                                                                   mp  91-94° C.                                       acetophenone                                                       71    70    [p-(hexadecyloxy)benzoyl]hydroxy-                                                                  white solid                                                methanesulfonic acid, sodium salt                                  72   p-fluoro-                                                                             [p-(p-fluorophenoxy)phenyl]glyoxal                                                                 mp 102-104° C.                               phenoxy                                                                        acetophenone                                                              73    72    [p-(p-fluorophenoxy)benzoyl]hydroxy-                                                               mp <300° C.                                         methanesulfonic acid, sodium salt                                  74     4    2,2-dihydroxy-4'-(p-methoxyphenoxy)-                                                               mp 115-119°                                         acetophenone                                                       75    74    hydroxy[p-(p-methoxyphenoxy)benzoyl]-                                                              mp 180-190°                                         methanesulfonic acid, sodium salt                                                                  (dec.)                                         76   n-butyloxy                                                                            p-butoxyphenyl) glyoxal                                                                            mp  82-87° C.                                acetophenone                                                              77    76    p-butoxybenzoylhydroxy-methanesulfonic                                                             white solid                                                acid, sodium salt                                                  78     5    4'-(p-bromophenoxy)-2,2-dihydroxy-                                                                 mp 120-125° C.                                      acetophenone                                                       79     6    [p-(p-tert-butylphenythio)benzoyl]-                                                                160° C.                                             hydroxy methanesulfonic acid, sodium                                                               (dec.)                                                     salt                                                               80     7    hydroxy[p-(p-methoxyphenythio)benzoyl]-                                                            mp 185-190°                                         methanesulfonic acid, sodium salt                                  81    71    [p-(decylamino)benzoyl]hydroxy-methane-                                                            white solid                                                sulfonic acid, sodium salt                                         82    13    2,2-dihydroxy-4'-m-tolyloxy-acetophenone                                                           mp  79-87° C.                           83    82    hydroxy[p-(m-tolyloxy)benzoyl]-methane-                                                            mp 190-195° C.                                      sulfonic acid, sodium salt                                         84    15    2,2-dihydroxy-4'-p-tolyloxy-acetophenone                                                           mp  92-99° C.                           85    84    hydroxy(p-tolyloxybenzoyl)-methane-                                                                mp 160-180° C.                                      sulfonic acid, sodium salt                                                                         (dec.)                                         86     8    [p-(p-fluorophenylthio)benzoyl]hydroxy-                                                            mp 180-200° C.                                      methanesulfonic acid, sodium salt                                                                  (dec.)                                         87     9    [p-(m-chlorophenoxy)benzoyl]hydroxy-                                                               mp 200-210° C.                                      methanesulfonic acid, sodium salt                                                                  (dec.)                                         88    87    4'-(m-chlorophenoxy)-2,2-dihydroxy-                                                                mp 138-150° C.                                      acetophenone                                                       89    14    hydroxy [p-(p-tolylthio)benzoyl]-                                                                  mp 180-200° C.                                      methanesulfonic acid, sodium salt                                                                  (dec.)                                         90   m-methoxy-                                                                            hydroxy [p-(m-methoxyphenoxy)benzoyl]-                                                             mp 160-180° C.                               phenoxyaceto                                                                          methanesulfonic acid, sodium salt                                                                  (dec.)                                              phenone                                                                   91     1    hydroxy (p-propoxybenzoyl)-methane-                                                                white solid                                                sulfonic acid, sodium salt                                         92    91    2,2-dihydroxy-4'-propoxy-acetophenone                                                              mp  79-81° C.                           93    10    (p-butylaminobenzoyl)hydroxy-methane                                                               white solid                                                sulfonic acid, sodium salt                                         94    11    [p-(p-chlorophenylthio)benzoyl]hydroxy-                                                            mp 205-220°                                         methanesulfonic acid, sodium salt                                                                  (dec.)                                         95    18    [p-(m-fluorophenoxy)benzoyl]hydroxy-                                                               mp <300° C.                                         methanesulfonic acid, sodium salt                                  96   4'-pentyl-                                                                            hydroxy (p-pentyloxybenzoyl)-methane-                                                              white solid                                         oxy-aceto-                                                                            sulfonic acid, sodium salt                                              phenone                                                                   97   o-bromo-                                                                              o-bromobenzoylhydroxy-methanesulfonic                                                              white solid                                         acetophenone                                                                          acid, sodium salt                                                  98    16    hydroxy[p-(octyloxy)benzoyl]-methane-                                                              white solid                                                sulfonic acid, sodium salt                                         99    98    2,2-dihydroxy-4'-(octyloxy)-acetophenone                                                           mp  75-79° C.                           100  p-hexadecyl-                                                                          4'-hexadecylamino-2,2-dihydroxy-aceto-                                                             mp  87-89° C.                                amino-aceto-                                                                          phenone                                                                 phenone                                                                   101    5    [p-(p-bromophenoxy)benzoyl]hydroxy-                                                                mp <300° C.                                         methanesulfonic acid, sodium salt                                  102  3-(4-methyl-                                                                          α-hydroxy-3-(4-methylphenoxy)-β-oxo-                                                    white solid                                         phenoxy)-                                                                             benzeneethanesulfonic acid, sodium salt                                 acetophenone                                                              103  m-(p-tert-                                                                            3-[4-(1,1-dimethylethyl)phenoxy]-                                                                  white solid                                         butylphenoxy                                                                          hydroxy- -oxo-benzeneethanesulfonic                                     phenoxy)                                                                              acid, sodium salt                                                       acetophenone                                                              104  p-decyl-                                                                              4-(decylamino)-α-oxo-benzeneacetalde-                                                        mp  88-90° C.                                amino-aceto-                                                                          hyde                                                                    phenone                                                                   105   100   4-(hexadecylamino)-α-hydroxy-β-oxo-                                                     mp 187-190° C.                                      benzeneethanesulfonic acid, sodium salt                            106  p-chloro-                                                                             p-chlorophenylglyoxal                                                                              mp 114-116° C.                               acetophenone                                                              107   106   (p-chlorobenzoyl)hydroxy-methanesulfonic                                                           white solid                                                acid, sodium salt                                                  108   35    (4-biphenylcarbonyl)hydroxy-methane-                                                               mp <150° C.                                         sulfonic acid, sodium salt                                         109   116   4'-chloro-α-hydroxy-β-oxo-4-biphenyl-                                                   mp <200° C.                                         ethanesulfonic acid, sodium salt                                   110   113   p-cyclohexylbenzoylhydroxy-methanesul-                                                             mp 175-190°                                         fonic acid, sodium salt                                                                            (dec.)                                         111   117   p-heptylbenzoylhydroxy-methanesulfonic                                                             mp 165-180° C.                                      acid, sodium salt                                                  112   119   hydroxy(4'-methyl-4-biphenylcarbonyl)-                                                             mp 250° C.                                          methanesulfonic acid, sodium salt                                                                  (dec.)                                         113  4'bromo-2,3-                                                                          p-bromobenzoylhydroxy-methanesulfonic                                                              mp 185-210° C.                               dihydroxy-                                                                            acid, sodium salt   (dec.)                                              acetophenone                                                              114   26    4'-(o-bromophenyl)2,2-dihydroxy-aceto-                                                             white solid                                                phenone                                                            115  2-bromo-4'-                                                                           2'-chloro-α-hydroxy-β-oxo-4-biphenyl-                                                   mp 173° C.                                   (o-chloro-                                                                            ethanesulfonic acid, sodium salt                                                                   (dec.)                                              phenyl)-                                                                       acetophenone                                                              __________________________________________________________________________

EXAMPLE 116 4'-(p-Chlorophenyl)-2,2-dihydroxy-acetophenone

A mixture of 9.28 g of 2-bromo-4'-(p-chlorophenyl)acetophenone (Example 22), 1.58 g of 89% phenol and 60 ml of dimethyl sulfoxide was stirred overnight then poured into ice water, giving a solid. The solid was triturated with methylene chloride and this solid was crystallized from acetone, giving the desired product as a beige solid, mp 275°-285° C.

Following essentially the procedure of Example 116 and using the indicated intermediates the products of Examples 117-119 given in Table V were obtained.

                  TABLE V                                                          ______________________________________                                              Inter-                                                                    Ex-  mediate                                                                   am-  Deri-                      Physical                                       ple  vation   Product           Constant                                       ______________________________________                                         117  24       4'-heptyl-2,2-dihydroxy-                                                                         mp 73.5-76.5° C.                                      acetophenone                                                     118  23       4-cyclohexyl-2,2-dihydroxy-                                                                      mp  87-105° C.                                        acetophenone                                                     119  19       2,2-dihydroxy-4'-p-tolyl-                                                                        mp 105-140° C.                                        acetophenone                                                     ______________________________________                                    

EXAMPLE 120 p[[hydroxy(2-naphthoyl)methyl]amino]benzoic acid

A mixture of 7.28 g of 2,2-dihydroxy-2'-acetonaphthone (prepared from 2'-acetonaphthone by the procedure of Example 31), 4.11 g of p-aminobenzoic acid, 150 ml of tetrahydrofuran and 50 ml of water was refluxed under nitrogen for 4 hours, then cooled and filtered. The filtrate was evaporated to a solid which was recrystallized from acetone:water, giving the desired product, mp 138°-148° C. (dec.).

Following the essential procedure of Example 120 and using the indicated intermediates, the products of Example 121 and 122 given in Table VI were obtained.

                  TABLE VI                                                         ______________________________________                                              Inter-                                                                    Ex-  mediate                                                                   am-  Deri-                       Physical                                      ple  vation   Product            Constant                                      ______________________________________                                         121  35       p-[α-hydroxy-p-phenyl-                                                                      mp 166° C.                                           phenacyl)amino]benzoic acid                                      122  30       p-[[2-(2-dibenzofuranyl)-1-                                                                       mp 217-219° C.                                       hydroxy-2-oxoethyl]amino]                                                                         (dec.)                                                      benzoic acid                                                     ______________________________________                                    

EXAMPLE 123 Phenyl glyoxal hydrate

A 200 g portion of phenyl glyoxal was distilled in a chilled flask containing 800 ml of water. The suspension was then diluted with 2.5 liters of water, cooled and the desired product collected as a white solid, mp 74°-80° C.

EXAMPLE 124 p-[(α-Ethoxy-p-phenylphenacyl)amino]benzoic acid

A 16.0 g portion of p-[(α-hydroxy-p-phenylphenacyl)amino]benzoic acid (Example 121) was heated in an oil bath at 140°-150° C. and 14 mm for 5 hours to a constant weight. A 10.0 g portion of this solid was stirred with 100 ml of 95% ethanol for 16 hours. The solid was collected and dried, giving the desired product as a light brown solid, mp 179° C.

EXAMPLE 125 N-(α- Hydroxy-p-phenylphenacyl)sulfanilic acid, sodium salt

A mixture of 1.14 g of 4-biphenylglyoxal (Example 35), 0.77 g of sulfanilic acid, 3.9 ml of 1N sodium hydroxide, 10 ml of water, 10 ml of ethanol and 10 ml of dioxane was stirred overnight, filtered and the filtrate evaporated. The solid was reduced to a powder, stirred with 75 ml of acetone and the solid collected. This solid was stirred with 75 ml of methanol, filtered and the filtrate evaporated. The residue was slurried in methanol and the mixture filtered. The filtrate was diluted with 4 volumes of ether and the solid collected giving the desired product as a tan solid, mp 285°-310° C. (dec.).

EXAMPLE 126 Dihydroxymethyl-5-phenyl-2-thienyl ketone

A solution of 97 ml of 2-bromothiophene in 500 ml of ether was prepared. A 100 ml portion of this solution was added to 36.5 g of magnesium and the mixture was stirred until the reaction started. The remaining 400 ml of solution was added slowly and then the mixture was stirred 1.5 hours. A 113 ml portion of cyclohexanone was added dropwise, then the mixture was allowed to stand overnight. A mixture of 150 ml of concentrated hydrochloric acid in 300 ml of water was added and the mixture was allowed to stand for 67 hours. An additional 100 ml of concentrated hydrochloric acid was added and the layers were separated. The aqueous layer was extracted with three 100 ml portions of ether. These extracts were combined with the organic layer, filtered and distilled at 100°-120° C., 5 mm giving an oil.

A 111 g portion of this oil and 334 g of chloranil in 500 ml of toluene were heated on a steam bath for 4 hours and then filtered. The filtrate was extracted with three 250 ml portions of 1N sodium hydroxide. The organic phase was filtered and evaporated to an oil which was distilled at 114°-117° C. giving an oil.

To a mixture of 39.8 g of the above oil in 200 ml of acetic anhydride was added 12 drops of perchloric acid. The mixture was stirred 3 hours, then poured onto ice. The solid was collected, dissolved in methylene chloride, dried and filtered through hydrous magnesium silicate. Hexane was added to the filtrate which was then evaporated on a steam bath until crystals started to form. The mixture was cooled and the solid collected.

A mixture of 10.1 g of the above solid, 5.83 g of selenium dioxide, 3 ml of water and 50 ml of dioxane was reacted as described in Example 31, giving the desired product as a light tan crystalline solid, mp 124°-128° C.

EXAMPLE 127 α-Hydroxy-β-oxo-5-phenyl-2-thiopheneethanesulfonic acid, sodium salt

Dihydroxymethyl-5-phenyl-2-thienyl ketone was converted to the desired sodium salt by the procedure of Example 32 as a light tan crystalline solid, mp 300° C. 

We claim:
 1. The method of treating diabetes mellitus in a mammal in need of such treatment which comprises administering to said mammal an effective antidiabetic amount of α-hydroxy-β-oxo-3-biphenylethanesulfonic acid, sodium salt.
 2. The method of treating hyperglycemia in a mammal in need of such treatment which comprises administering to said mammal an effective hypoglycemic amount of α-hydroxy-β-oxo-3-biphenylethanesulfonic acid, sodium salt. 